The brain has its own secret stash

(Carl Hall, The San Francisco Chronicle, May 20, 2001)

Even if you have never smoked a joint in your life, a cannabis-like substance occupies a special niche in your brain, fine-tuning the nerve connections that control memory and most other thought processes.

New research into how these so-called "endogenous cannabinoids" work may help scientists understand what goes on inside the heads of those who smoke pot -- which floods the nervous system with far more of the active ingredient than the brain can supply on its own.

Last week's U.S. Supreme Court ruling against the medicinal use of marijuana came as brain scientists were celebrating profound new discoveries about how cannabis works in our heads.

The landmark studies, published recently in the journals Nature and Neuron by scientists at the University of California at San Francisco, Harvard Medical School and Kanazawa Medical University in Japan, suggest the brain cooks up its own marijuana-like ingredients in order to tweak the all- important connections that link nerve cells.

Two of these marijuana-like substances have been discovered so far, docking in the very same nerve-cell receptors used by THC, the active ingredient in pot.

It's as if the brain has its own secret stash. But despite years of research, scientists had no clear idea until now what its purpose might be.

"Were we built to smoke marijuana?" wondered Jeff Isaacson, an assistant professor at the University of California at San Diego, who contributed to the latest findings by UC San Francisco graduate student Rachel Wilson and neuroscientist Roger Nicoll.

They set out to discover how nerve cells "talk back" to one another in a brain region called the hippocampus, which is crucial in memory and learning -- and, not coincidentally, one of the principal areas affected by smoking pot.

The back talk involved is actually a feedback loop that allows a nerve cell, or neuron, receiving an impulse from another neuron to fire back its own signal, thus modifying critical neurochemical activity at the source.

This so-called "retrograde signaling" is one key way neurons can dial into one another, allowing effective communication to take place at the cellular level.

There are essentially two kinds of brain cells, according to Stanford University neuroscientist Dan Madison. There are the principal cells that make up what he likened to a superhighway system of long-range information movement, and there are "interneurons," which are like traffic signals along that highway.

"Cannabinoids are a way for the principal cells to regulate the traffic lights," Madison said.

After two years of laboratory study and frustrating dead ends, Wilson and Nicoll found that the role of the brain's cannabis is to make the feedback system work. Harvard researchers, working independently, found an essentially identical role for endogenous cannabinoids in another part of the brain, called the cerebellum, which helps to control motor function.

"It's a way for a nerve cell to adjust the gain or intensity of the information coming into it," Nicoll said. "It turns up the amplifier, in a way, and allows more input to get through."

These adjustments seem to have an important role in the brain's uncanny ability to synchronize the firing of nerve cells scattered throughout the brain, linking behavior with mood and memory with vision or hearing. Thousands of signals thus become molded into vast oscillations, helping the brain bind together different aspects of perception into something we can experience as a coherent state of mind -- a feeling of being in love, perhaps, when we look at someone.

If that's the case, the implications for marijuana smokers seem rather profound.

Marijuana receptors are just about everywhere inside our skulls, but the brain's natural cannabis is present in minute amounts, and its effects are subtle: a fleeting and localized shift in brain chemistry in particular areas of the nervous system.

When you smoke a joint, researchers said, you essentially swamp that whole system for however long the buzz lasts by flooding the brain with THC. This may help to explain why marijuana users report the drug has such diverse and often idiosyncratic effects on mood, memory, appetite, vision, pain and motor control.

Some users report an odd stretching of their sense of time. Others make connections -- humorous, sometimes -- between things that normally don't seem related. And memory is clearly impaired, as is motor function.

Such effects start to make sense, researcher Wilson said, in light of the new insights into how natural cannabinoids function

"We suspect that marijuana is sort of hijacking the system, doing what the brain normally does but in overdrive," she said.

Marijuana researchers have found no reliable evidence of permanent damage arising from this hijacking, and the latest experiments are said to be essentially neutral as to the merits of allowing medicinal use of pot.

The new brain findings may help drug researchers find ways to mimic pot's effects, perhaps leading to development of drugs that similarly modify synaptic connections but in a more controlled way.

The research also gives scientists a topic with which they can liven up their social lives when they venture outside the lab.

Nicoll, for one, likes to look audiences right in the eye, wag his finger and insist that during the entire two-year research project he "never once inhaled."

"Marijuana and the brain is a fun field to be in," Isaacson, Nicoll's former graduate student, said. "You talk about this with people at parties, and they're actually interested."

Copyright © 2001 by The San Francisco Chronicle

E-mail Carl Hall at chall@sfchronicle.com